Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Mol Cell. 2020 Jun 18;78(6):1086-1095. doi: 10.1016/j.molcel.2020.04.023. Epub 2020 May 13.
Transcription is epigenetically regulated by the orchestrated function of chromatin-binding proteins that tightly control the expression of master transcription factors, effectors, and supportive housekeeping genes required for establishing and propagating the normal and malignant cell state. Rapid advances in chemical biology and functional genomics have facilitated exploration of targeting epigenetic proteins, yielding effective strategies to target transcription while reducing toxicities to untransformed cells. Here, we review recent developments in conventional active site and allosteric inhibitors, peptidomimetics, and novel proteolysis-targeted chimera (PROTAC) technology that have deepened our understanding of transcriptional processes and led to promising preclinical compounds for therapeutic translation, particularly in cancer.
转录是由染色质结合蛋白的协调功能通过表观遗传调控的，这些蛋白可紧密控制主转录因子、效应物和支持性管家基因的表达，这些基因对于建立和传播正常和恶性细胞状态是必需的。化学生物学和功能基因组学的快速发展促进了靶向表观遗传蛋白的探索，从而产生了靶向转录的有效策略，同时降低了对未转化细胞的毒性。在这里，我们回顾了传统活性位点和别构抑制剂、肽模拟物以及新型的蛋白水解靶向嵌合体（PROTAC）技术的最新进展，这些进展加深了我们对转录过程的理解，并为治疗转化，特别是癌症，带来了有前景的临床前化合物。
